Bioterrorism agents are bacteria, viruses, and toxins that are dispersed deliberately in an environment to cause disease or death in humans or animals. Bioterrorism agents include, but are not limited to, Bacillus anthracis (anthrax), Yersinia pestis (plague), Variola major (smallpox), tick-borne encephalitis virus (TBEV) (tick-borne encephalitis), and Ebola virus (Ebola). Bioterrorism agents can also include biotoxins, which are toxins produced by certain biological organisms. Exemplary biotoxins are botulinum toxin, which is produced by the bacterium Clostridium botulinum, and ricin, which is isolated from castor oil seeds.
The immune system has evolved two general strategies for combating infections from bioterrorism agents such as anthrax. A rapid “innate” immune response is induced when Toll-like receptors (TLR) on host cells interact with highly conserved pathogen associated molecular patterns (PAMPs) expressed by infectious microorganisms (Marrack and Kappler, Cell 76:323, 1994; Medzhitov and Janeway, Cur. Op. Immunol. 9:4, 1997). The resultant production of polyreactive antibodies and immunostimulatory cytokines check the pathogen's early proliferation and spread (Marrack and Kappler, Cell 76:323, 1994; Medzhitov and Janeway, Cur. Op. Immunol. 9:4, 1997; Medzhitov and Janeway, Cell 91:295, 1998). A subsequent antigen-specific immune response is then generated against determinants unique to the pathogen that helps to eradicate the remaining organisms and provide long-lasting protective memory.
Vaccination can be used to protect against the effects of some bioterrorism agents. For example, in the case of anthrax, “protective antigen” (PA) is necessary for vaccine immunogenicity (Ivins et al., Infect. Immun. 60:662, 1992; Welkos and Friedlander, Microb. Pathog. 5:127, 1998). Antibodies against PA prevent anthrax toxin from binding to host cells, thus abrogating toxicity (Little and Ivins, Microbes. Infect. 1:131, 1999). Additionally, antibodies to PA can inhibit the germination of spores while improving their phagocytosis and killing by macrophages (Welkos et al., Microbiology 147:1677, 2001). Unfortunately, the currently licensed human anthrax vaccine (AVA) requires six vaccinations over eighteen months followed by yearly boosters to induce and maintain protective anti-PA titers (Pittman et al., Vaccine 20:1412, 2002; Pittman et al., Vaccine 20:972, 2001). In some vaccinees, this regimen is associated with undesirable local reactogenicity (Pittman et al., Vaccine 20:972, 2001).
Thus, there exists a need for agents that prevent or treat infections caused by bioterrorism agents, or that increase the immunogenicity of a vaccine against a bioterrorism agent, in order to treat or prevent infections in individuals exposed to or at risk of exposure to bioterrorism agents.